A population of large pyramidal cells in layer 5 of the mammalian neocortex has been identified who are more excitable than other cortical neurons, due to a relatively weak GABAergic inhibitory synaptic input onto these cells. A relatively weak inhibitory synaptic input leads to un-checked firing and makes these cells more likely to initiate epileptiform discharges such as those occurring during seizures, and more susceptible to neurodegeneration as a result of excitotoxicity. The mechanisms behind this weak inhibition are not well understood. We have found previously, that the duration of evoked GABAA receptor-mediated post-synaptic potentials (IPSPs) is shorter in layer 5 compared to layer 2/3 pyramids. The importance of IPSP duration in determining the efficacy of inhibitory synaptic input is illustrated by the fact that an increase in duration of inhibitory synaptic currents is believed to be the mechanism of action of a variety of therapeutic drugs used as anxiolitics, anti-epilepsy medication and certain anesthetics. Although several theories have been proposed there is no consensus on the factors that control the duration of IPSPs in cortical neurons. The long- term objective of this application is to identify the main factors that determine the time course of GABAA-receptor-mediated IPSPs in the neocortex and to examine the nature of the differences in IPSP duration between population of cortical neurons. A better understanding of these actors could suggest new ways in which the efficacy of inhibition can be enhanced, and this could lead to the development of new drug therapies for epilepsy of the prevention of neurodegeneration due to excitotoxicity in a variety of neurological disorders. Four factors will be examined, namely the intrinsic membrane properties of the post-synaptic membrane, the location on the post-synaptic membrane of the inhibitory synaptic terminals, the time course of GABA in the synaptic cleft, and the properties of the post-synaptic receptor channels themselves. These studies are designed such that the contribution of each factor can be studied in isolation of the others. For this purpose in vitro slices of rat neocortex will be utilized, using whole-cell patch clamp recordings of spontaneous and evoked inhibitory synaptic activity in visually identified neurons and rapid GABA agonist applications to excised outside-out membrane patches for the study of single-channel properties.